PH sensitive surgical tool

ABSTRACT

Embodiments include methods, systems, and apparatus for identification, detection, and removal of cancerous cells from a patient. The apparatus includes an apparatus handle. The apparatus also includes a display including a pH measurement result. The apparatus also includes an apparatus tip including a reference electrode and a plurality of sensing surfaces, wherein each of the plurality of sensing surfaces is connected to a base of a bipolar junction transistor (BJT) device. The BJT device further includes a collector and an emitter. The apparatus also includes automation circuitry including a processing unit in communication with the apparatus tip and the display. The plurality of sensing surfaces includes a conducting material.

BACKGROUND

The present invention relates in general to surgical instruments, andmore specifically, to a pH sensitive surgical tool and relatedoperations for real-time identification and removal of cancerous cells.

When a patient tissue is diagnosed as cancerous, patients can undergosurgical procedures to have the affected tissue removed. To prevent orminimize recurrence and renewed growth of a cancerous region, it isoften necessary to remove all the cancerous cells. For the surgeon, itis not possible to distinguish every cancerous cell from everynon-cancerous cell with the naked eye. Thus, other modes of detectionare needed to determine whether all the cancerous cells have beenexcised in a surgical procedure. For instance, in a conventionalsurgical procedure, the surgeon removes a portion of tissue thatpotentially contains cancerous cells and sends the portion of tissue toa pathology laboratory to determine whether it is cancerous. If it isdetermined to be cancerous, the surgeon removes additional tissue in asubsequent surgical excision, sometimes in the same day. In some cases,a patient and surgical team can wait in the middle of surgery forpathology results to arrive before the surgical procedure can eithercontinue or be concluded. Multiple iterations of the surgical procedurecan be needed to remove affected tissue in its entirety.

A need exists to distinguishing non-cancerous tissue from canceroustissue during a surgical procedure to improve patient comfort and toimprove patient outcomes. A need also exists to identify cancerous cellswith high spatial resolution during surgery.

SUMMARY

In accordance with one or more embodiments of the invention, a surgicalapparatus for identification and removal of cancerous cells is provided.The apparatus includes a display including a pH measurement result. Theapparatus also includes an apparatus tip including a reference electrodeand a plurality of sensing surfaces, wherein each of the plurality ofsensing surfaces is connected to a base of a bipolar junction transistor(BJT) device. The BJT device further includes a collector and anemitter. The apparatus also includes automation circuitry including aprocessing unit in communication with the apparatus tip and the display.The plurality of sensing surfaces includes a conducting material. Theseembodiments of the invention can advantageously allow real-timeidentification of cancerous tissue and thereby improve cancer treatmentoutcomes.

In accordance with one or more embodiments of the invention, a surgicalapparatus for identification and removal of cancerous cells is provided.The apparatus includes a display including a pH measurement result. Theapparatus also includes an apparatus tip including a reference electrodeand a plurality of field effect transistor (FET) devices. The FETdevices include a gate dielectric including a FET sensing surface, asource, a drain, and a substrate. The apparatus also includes automationcircuitry including a processing unit in communication with theapparatus tip and the display. These embodiments of the invention canadvantageously allow real-time identification of cancerous tissue andthereby improve cancer treatment outcomes.

In accordance with one or more embodiments of the invention, a surgicalapparatus for identification and removal of cancerous cells includes adisplay including a pH measurement result, a tip including a referenceelectrode and a plurality of sensing surfaces, and optionally a scalpelblade. This embodiment of the invention can provide enhancedfunctionality to conventional surgical devices, for instance by allowingidentification and removal of cancerous tissues with a single surgicalinstrument.

In accordance with another embodiment, a surgical apparatus foridentification and removal of cancerous cells includes a displayincluding a pH measurement result, a tip including a reference electrodeand a plurality of sensing surfaces, and optionally a forceps. Thisembodiment of the invention can provide enhanced functionality toconventional surgical devices, for example by providing a pH sensingsystem on an instrument likely to be used in the removal of cancerouscells, reducing the need to exchange instruments during a surgicalprocedure.

In accordance with another embodiment, a surgical apparatus optionallyincludes a BJT-pH sensor array. A BJT-pH sensor array, for example, canadvantageously provide a higher resolution sensing capacity than anapparatus in which a BJT-pH sensor array is not included by reducing therequired surface area for functional components on the tip.

In accordance with a further embodiment, a method for identification andremoval of cancerous tissue includes placing an apparatus for removal ofcancerous cells in contact with an extracellular medium associated witha tissue of interest on a patient. The apparatus includes a display, anapparatus tip including a pH sensor, and automation circuitry includinga processing unit in communication with the apparatus tip and thedisplay. The method also includes measuring a local pH of theextracellular medium with the apparatus. The method also includes, basedupon a determination that the local pH is acidic, excising the tissue ofinterest. Methods according to such embodiments of the invention canreduce the time and expense associated with cancerous tissue excision,for example by reducing the need for external laboratory testing andreducing the need for follow-on surgical procedures in cases where alltissue is not removed in a first surgery.

In accordance with another embodiment, a method for removal of canceroustissue optionally includes measuring a collector current from a BJTcollector. A collector current can, for example, lead to acomputationally inexpensive pH calculation.

In accordance with another embodiment, a method for removal of canceroustissue optionally includes measuring a drain current from a FET-pHsensor with a FET sensing surface applied to extracellular medium of atissue of interest. A drain current measurement can, for example, alsolead to a computationally inexpensive pH calculation.

In accordance with another embodiment, a method for removal of canceroustissue optionally includes calibrating a pH sensor. Calibrating a pHsensor can advantageously improve the accuracy of a resultant pHmeasurement and, thus, provide increased confidence in removal ofcancerous tissues.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter of the present invention is particularly pointed outand distinctly claimed in the claims at the conclusion of thespecification. The foregoing and other features and advantages of theone or more embodiments described herein are apparent from the followingdetailed description taken in conjunction with the accompanying drawingsin which:

FIG. 1 depicts a surgical apparatus for identification of cancerouscells with high spatial resolution according to one or more embodimentsof the present invention.

FIG. 2 depicts a cross-sectional side view of a BJT-pH sensor for use inthe removal of cancerous cells according to one or more embodiments ofthe present invention.

FIG. 3 depicts a cross-sectional side view of a portion of a pH sensorarray for use in the removal of cancerous cells according to one or moreembodiments of the present invention.

FIG. 4 depicts a cross-sectional side view of a portion of an apparatusfor removal of cancerous skin cells in operation according to one ormore embodiments of the present invention.

FIG. 5 is a chart depicting collector current versus the differencebetween the voltage applied at the base and the voltage applied at theemitter of an exemplary BJT-pH sensor for use in embodiments of thepresent invention.

FIG. 6 is a chart depicting collector current at a fixed voltage of 0.7V versus pH for the exemplary BJT-pH sensor represented in FIG. 5.

FIG. 7 depicts a storage system for an apparatus for removal ofcancerous skin cells according to one or more embodiments of the presentinvention.

FIG. 8 depicts a cross-sectional side view of a FET-pH sensor for use inthe removal of cancerous skin cells according to one or more embodimentsof the present invention.

FIG. 9 is a chart depicting drain current versus gate voltage of anexemplary FET-pH sensor for use in embodiments of the present invention.

FIG. 10 is a chart depicting drain current at a fixed gate voltage of0.55 V versus pH for the exemplary FET-pH sensor represented in FIG. 9.

FIG. 11 is a flow diagram of a method for removing cancerous tissueaccording to one or more embodiments of the present invention.

FIG. 12 is a flow diagram of a method for identifying cancerous tissuewith a surgical apparatus in accordance with one or more embodiments ofthe present invention.

FIG. 13 is a block diagram illustrating one example of a processingsystem in accordance with an exemplary embodiment.

DETAILED DESCRIPTION

Systems and methodologies for identification and removal of canceroustissue are provided. Removal of cancerous tissue frequently involvessurgical extraction of the cancerous tissue. Conventionally, surgeonsuse visual and palpation methods to identify cancerous regions to beremoved during surgery and to distinguish these regions fromnon-cancerous regions. While a patient is under anesthesia, surgeons cansend out tissue samples to pathology labs to determine whether allcancerous cells of a region have been removed. Failure to remove allcancerous cells can lead to proliferation of remaining cancer cells and,thereby, re-occurrence of cancer.

In surgery, for instance, a surgeon can remove some tissue containingcancerous cells and send the tissue to a pathology lab. The patient canbe sent home to heal with an uncertain surgical outcome, or in somecases wait with an open wound while a report is generated and returnedto the clinician that details if and where any cancerous tissue remains.The clinician, after receiving the report can then return to the patientto remove more tissue, send newly excised tissue to the pathology lab,and repeat the remainder of the process. In some cases, severaliterations could be conducted before all cancerous tissue is removed.

Conventional surgical methods of tumor removal are semi-quantitativewith low spatial resolution. Moreover, conventional methods can lack areal-time identification of the boundary of a cancerous region.Accordingly, incomplete removal of a tumor can result, requiring asecondary surgery for treatment.

A need exists for surgical instruments and methods with high spatialresolution for cancerous cell removal. There is a need for improvedinstruments and methods for removal of cancerous tissues with real-timeidentification of cancerous skin cells.

Embodiments of the invention can overcome drawbacks associated withconventional methods. Tumor cells, such as medium-sized tumor cells, canbe associated with an extracellular medium having a lower pH than theextracellular medium of healthy cells. Embodiments of the inventioninclude a surgical tool with a solid-state label free pH sensor that canidentify and define a tumor region, including during surgery.Embodiments of the invention can leverage the pH difference betweencancerous and non-cancerous cells and, thereby, provide quantitativeidentification of cancerous skin cells in real-time. Thus, embodimentsof the invention provide improved cancer treatment outcomes and areduced incidence of secondary surgery.

Turning now to a more detailed description of embodiments of the presentinvention, FIG. 1 depicts a surgical apparatus 300 for identification ofcancerous cells with high spatial resolution according to one or moreembodiments of the present invention. The apparatus 300 includes ahandle 302 and an apparatus tip 308. The handle 302 and tip 308 can beany shape, such as rectangular, cubic, or cylindrical and can be thesame size or differing sizes. The tip 308 has a length L and width Wthat can be of a size suitable for tumor removal applications. In someembodiments of the invention, the tip 308 has a width that is 2 to 10mm, for instance 2 to 5 mm or 2 to 3 mm. In some embodiments of theinvention, the tip 308 has a length that is 2 to 10 mm, for instance 2to 5 mm or 2 to 3 mm. The tip 308 can include one or more pH sensors310. In some embodiments of the invention, the tip 308 includes an arrayof pH sensors 310. The pH sensors 310 can be solid state device basedsensors. In some embodiments of the invention, the pH sensors 310 arebipolar junction transistor (BJT) based pH sensors. In some embodimentsof the invention, the pH sensors 310 are field effect transistor (FET)based pH sensors. In some embodiments of the invention, the pH sensors310 include multiple sensors in a pH sensor array. The apparatus 300 caninclude automation circuitry 304. In some embodiments of the invention,the circuitry 304 serves to calibrate and measure pH in real-time. Thecircuitry 304 can include, for instance, data storage, processingunit(s), and wireless data transmission components. The circuitry 304can communicate with the tip 308, including directly or indirectly withthe pH sensors, and with a data display 306. In some embodiments of theinvention, the data display 306 and automation circuitry 304 areincluded in the handle 302. For example, the automation circuitry 304can be embedded within the handle 302 and the display unit 306 can be onthe surface of the handle 302. In some embodiments of the invention, notshown in FIG. 1, the display 306 is external to the apparatus. Forexample, the display 306 can be included within a smartphone, smartwatch, laptop computer or PC. The data display 306 can display any dataprovided by the apparatus, including, but not limited to, a measured pH,position, battery life, memory capacity, and the like.

In some embodiments of the invention, the display includes a pHmeasurement result. The pH measurement result can include a quantitativeor a qualitative indication of local pH. For example, a quantitativeindication can include a numerical display of a pH value. A qualitativeindication, for instance, can include a signal representing a pH aboveor below a threshold value. For example, a light of a particular colorcan signal a relatively high local pH, thus signaling to a surgeon thepresence of cancerous tissue. The display can also include spatialinformation. For example, each sensing surface measures the local pHnear its spatial vicinity. Thus, the area of the sensing surface isproportional to the spatial resolution of the sensor and the apparatuscan, accordingly, provide quantitative spatial data to the display.

In some embodiments of the invention, the apparatus 300 is a stand-alonetool. In some embodiments of the invention, the apparatus 300 isincluded within or attached to another apparatus. For instance, theapparatus 300 can be attached to scalpel or forceps. The apparatushandle can be attached, for example, to the tip and to a scalpel orforceps, for instance, such that the handle is shared. In someembodiments of the invention, for example, a surgeon can both measure pHand perform a surgical function, such as tissue excision ormanipulation, without the need to exchange tools. For instance, ascalpel can include a blade on one end and a tip on the opposite end or,a scalpel blade and tip on the same end of the apparatus such that pHmeasurement and excision of tissue involves minimal manipulation of thesurgical apparatus.

The tip 308 of the apparatus 300, in operation, can be applied to atissue sample to distinguish between cancerous (or tumor) regions andnon-cancerous or (non-tumor) regions. Each BJT based pH sensor 310 ofthe tip can measure the collector current and, after calibration, thecollected current can be associated with a local pH having a spatialresolution equal to the sensing surface dimensions. A relatively acidiclocal pH can be indicative of a cancerous region, whereas a pH ofreduced relative acidity (a higher pH) can be associated with anon-cancerous region. By moving the tip 308 across a tissue sample, asurgeon can distinguish between areas of differing pH in real-time and,thereby, distinguish between cancerous and non-cancerous regions oftissue. Thus, in operation, an apparatus according to one or moreembodiments of the invention can enable a surgeon to quantitativelydistinguish between cancerous regions to be extracted and non-cancerousregions that do not require excision in real-time.

FIG. 2 depicts a cross-sectional side view of a BJT-pH sensor 400 foruse in the identification or detection of cancerous cells according toone or more embodiments of the invention of the present invention.BJT-pH sensor 400 includes a silicon substrate 404 and a collector 406positioned on the silicon substrate 404. The BJT-pH sensor 400 alsoincludes a base 416 formed on the collector 406. An emitter 414 can beformed on the base 416.

The BJT-pH sensor 400 can be an NPN type BJT or a PNP type BJT device.The selection of materials and dopant polarity can vary depending onwhether the BJT-pH sensor is an NPN type or PNP type. For example, anNPN BJT can include a heavily doped n-type emitter 414, a p-type dopedbase 416, and a p-type doped collector 406. In some embodiments of theinvention, the BJT-pH sensor 400 is a PNP type including, for instance,a heavily doped p-type emitter 414, an n-type doped base 416, and ann-type doped collector 406.

Silicon substrate 404 can include silicon or doped silicon. For example,the substrate 404 can include undoped silicon, p-type doped silicon orn-type doped silicon.

Collector 406 can include, for example, silicon, including doped orheavily doped silicon (i.e., more heavily doped than the substrate 404,which can be doped or undoped). The dopant polarity can be opposite tothat of the substrate 404. For example, if the substrate 204 includesp-type doped silicon, the collector can include n-type heavily dopedsilicon. In some embodiments of the invention, collector 406 includesn-type heavily doped gallium arsenide (GaAs).

A base 416 can be formed on the collector 406. Base 416 can include, forinstance, a doped silicon, such as silicon germanium (SiGe). In someembodiments of the invention, the silicon germanium is doped, or heavilydoped (i.e., more heavily doped than the substrate 404). The dopantpolarity can be opposite to that of the collector 406. For example, ifthe collector 206 includes n-type doped or heavily doped silicon, thebase 416 can include p-type doped or heavily doped silicon germanium.

An emitter 414 can be formed on the base 416 and can include, forinstance, silicon, polysilicon, or gallium arsenide. Emitter 414 caninclude polysilicon that is very heavily doped (i.e., doped more heavilythan the collector 406 or the base 416).

As is further illustrated in FIG. 2, in one or more embodiments of thepresent invention BJT-pH sensor 400 includes a reference electrode 402and a sensing surface 408. The reference electrode 402 can include, forexample, a silver chloride reference electrode. The sensing surface 408and reference electrode 402 can have surfaces externally accessible tothe BJT-pH sensor such that they can be placed into contact with tissueand the extracellular medium associated with tissue. In some embodimentsof the invention, the sensing surface(s) 408 are accessible to tissuewhen the BJT-pH sensor is included within a surgical apparatus forremoval of cancerous cells according to one or more embodiments of thepresent invention. Base 416 can be electrically connected to the sensingsurface 408 via a metal line 418. Metal line 418 can be a conductivemetal wire, such as a tungsten wire.

The reference electrode 402 and sensing surface 408 are positioned on orembedded within an oxide layer 410 and each have an accessible surfacefor pH measurement. Oxide layer 410 can be composed of any oxide-baseddielectric or insulating material that can be used for insulation insemiconductor devices, including but not limited to silicon dioxide,aluminum oxide, hafnium oxide, and combinations thereof.

The sensing surface 408 can have any shape. The sensing surface 408 canhave a length or diameter of 5 to 15 micrometers (μm), for example from5 to 10 μm or from 5 to 8 μm. In some embodiments of the invention, thesensing surface 408 has a length or diameter smaller than the diameterof a cell. For example, a cell can have a diameter of 10 μm and thesensing surface can have a diameter of 5 μm. The sensing surface 408 canbe planar or have a three-dimensional shape. The area of the sensingsurface can be directly related to the spatial resolution of the pHsensing apparatus.

In some embodiments of the invention, the sensing surface 408 includesconducting titanium nitride (TiN). The sensing surface 408 can becomposed of any pH sensitive conducting material. In some embodiments ofthe invention, for example, sensing surface 408 includes a TiN filmsputter deposited over a metal line 418. The sensing surface 408 caninclude, in some embodiments of the invention, platinum, rutheniumoxide, iridium oxide, conductive carbon, or combinations thereof.

In some embodiments of the present invention, a surgical apparatusincludes a plurality of BJT-pH sensors, wherein each BJT-pH sensorincludes one sensing surface. In some embodiments of the invention, asurgical apparatus includes a BJT-pH sensor array.

FIG. 3 depicts a cross-sectional side view of a portion of a pH sensorarray 450 for use in the removal of cancerous cells according to one ormore embodiments of the present invention. The array 450 includes aplurality of sensing surfaces 408. Each of the plurality of sensingsurfaces can be connected to a metal line 418. The plurality of sensingsurfaces 408 and metal lines 418 can be embedded within an oxide layer410, such that the sensing surfaces 408 have a surface that can beaccessible to a tissue sample. The array 450 includes a referenceelectrode 402. In some embodiments of the invention, the array 450includes one reference electrode 402. In some embodiments of theinvention, not shown in FIG. 3, the array 450 includes a plurality ofreference electrodes 402.

The pH sensor array 450 can include other components, such as each ofthe components that are included in a BJT-pH sensor 400 according to oneor more embodiments of the invention. For example, the plurality ofsensing surfaces 408 can each be electrically connected to a base 406via the plurality of metal lines 418. In some embodiments of theinvention, each base 416 is positioned on a collector 406, which ispositioned on a substrate 404. In some embodiments of the invention, apH sensing array includes a plurality of emitters 414.

In operation, in some embodiments of the invention, a surgical apparatusfor removal of cancerous cells is brought into contact with cells andthe extracellular medium of a tissue of interest in an operation forremoval of cancerous cells. The tissue of interest can include cancerouscells and non-cancerous cells in proximity to the cancerous cells.

FIG. 4 depicts a cross-sectional side view of a portion of an apparatusfor removal of cancerous skin cells in operation according to one ormore embodiments of the present invention. As is shown, a sensingsurface 408 is brought in contact with extracellular medium 504surrounding a plurality of cells 502. Although FIG. 4 depicts a BJT-pHsensor, in some embodiments of the invention, a sensing surface is asurface of a FET-pH sensor. The cells 502 can be cells of tissue ofinterest and can include, for instance, cancerous and non-cancerouscells. The apparatus in operation can measure the local pH of theextracellular medium 504 to determine if the extracellular medium 504 isin a tumor environment or a non-tumor environment. An acidic pH can beindicative of a tumor environment, including an environment local to oneor more cancerous cells.

In operation, a collector 406 and reference electrode 402 can beinitially set at a voltage of zero. An emitter 414 can be held at aconstant voltage and current is the sensing signal. In some embodimentsof the invention, an apparatus includes an NPN BJT device and theemitter voltage is held at a constant voltage less than 0 Volts (V). Insome embodiments of the invention, an apparatus includes an NPN BJTdevice and the emitter voltage is held at a constant voltage greaterthan 0 V.

In some embodiments of the invention, an apparatus is calibrated. Forexample, an apparatus including a BJT-pH sensor can be calibrated todetermine sensing signal dependence on applied voltage and pH. Aftercalibration, collector current can be measured at a fixed voltage and pHcalculated therefrom.

Sensing of pH with a BJT-pH sensor can be performed in accordance knownmethods. For example, the principle of sensing can be determined bymeasuring the sensing current at the device collector, following theEbers-Moll equation as follows:I _(C) =I _(o) exp{q(V _(B)+ψ_(s) −I _(B) R−V _(E) /kT}.

wherein I_(C) is the collector current I_(o) is a constant dependentupon device parameters, q is the electronic charge, V_(B) is the basevoltage applied at the reference electrode, ψ_(s) is the sensing surfacepotential, I_(B) is the base current flowing through the solution, R isthe resistance of the solution, V_(E) is the emitter voltage, k is theBoltzmann constant, and T is the device temperature. As is known anddescribed elsewhere, I_(B)R can be treated as negligible. Thus, thesystem can be calibrated with known pH buffer solutions and measuringsensing current I_(C) as a function of applied voltageV_(BE)=(V_(B)−V_(E)).

FIG. 5 is a chart depicting collector current versus the differencebetween the voltage applied at the base and the voltage applied at theemitter of an exemplary BJT-pH sensor for use in embodiments of thepresent invention. FIG. 5 demonstrates sensing signal (I_(C)) dependenceon applied voltage and pH. Buffered solutions having known pH values of4, 5.4, 6, 7, and 8 can each be applied to a BJT-pH sensor, such as aBJT-pH sensor of a tip of an apparatus for use in embodiments of thepresent invention. I_(C) can be measured and plotted against the appliedvoltage V_(BE). FIG. 5 illustrates a BJT pH sensor with a voltage per pHunit of 58 millivolts (mV).

In some embodiments of the invention, calibration results are used todetermine a local pH of a tissue of interest. For example, a fixedapplied voltage can be applied to a system having one or more BJT-pHsensors and a sensing signal (I_(C)) can be measured in real time. Fromthe sensing signal, pH can readily be calculated with the calibrationresults.

FIG. 6 is a chart depicting collector current at a fixed voltage of 0.7V versus pH for the exemplary BJT-pH sensor represented in FIG. 5.Application of a fixed voltage and measurement of sensing signal canprovide a pH measurement in real time.

As is illustrated in FIGS. 5 and 6, the sensing signal of embodiments ofthe invention of the invention can increase up to ten units per pH unit,resulting in a system with high sensitivity. Moreover, sensitivity inembodiments of the invention is independent of salt concentrations.

FIG. 7 depicts a storage system 550 for an apparatus for removal ofcancerous skin cells according to one or more embodiments of the presentinvention. The storage system 550 includes a cap 552 covering a portionof the tip 308. In some embodiments of the invention, the cap 552 coverspH sensors of the system (not shown in FIG. 7). In some embodiments ofthe invention, the cap 552 holds an aqueous storage solution, such as asaline solution, or a buffered pH-saline solution (not shown), incontact with the pH sensors (not shown). Providing a cap 552 with anaqueous solution such as a pH buffer including 1-5 millimolar (mM) NaClcan advantageously protect or preserve the pH sensors of embodiments ofthe present invention. In some embodiments of the invention, the storagesystem 550 results in minimum signal drifts or can have improvedsettling times over the settling times of dry sensing surfaces, whichcan be on the order of several minutes.

FIG. 8 depicts a cross-sectional side view of a FET-pH sensor 600 foruse in the removal of cancerous skin cells according to one or moreembodiments of the present invention. The FET-pH sensor 600 includes aFET silicon substrate 602 and a source 604 and drain 606. FET Siliconsubstrate 602 can include silicon or doped silicon, for example thesubstrate 602 can include a silicon-on-insulator wafer (SOI) withlightly doped p-type silicon. The FET-pH sensor 600 can include an oxidelayer 610. The FET-pH sensor 600 includes a gate dielectric 608 atop theFET silicon substrate 602. The FET-pH sensor includes a FET referenceelectrode 612. The FET reference electrode 612 can include, for example,silver chloride. The gate dielectric 608 and FET reference electrode 612can be embedded within or on top of the oxide layer 610.

Each of the gate dielectric 608 and the FET reference electrode 612 canhave surfaces externally accessible to the FET-pH sensor such that theycan be placed into contact with tissue and the extracellular mediumassociated with tissue and extracellular medium associated with tissue.In some embodiments of the invention, the externally accessiblesurface(s) of the gate dielectric 608 and the FET reference electrode612 are accessible to tissue when the FET-pH sensor is included within asurgical apparatus for removal of cancerous cells according to one ormore embodiments of the present invention.

Source 604, and drain 606 can be composed of materials conventionallyused for such components in FET-devices and can be formed byconventional methods. Source 604 and drain 606 are formed on opposingsides of the gate dielectric 608. For example, source 604 and drain 606can be formed with an epitaxial growth process to deposit a crystallinelayer onto the FET substrate 602. The epitaxial silicon, silicongermanium, and/or carbon doped silicon (Si:C) can be doped duringdeposition by adding a dopant or impurity to form a silicide. Theepitaxial source/drain can be doped with an n-type dopant or a p-typedopant, which depends on the type of transistor. In some embodiments ofthe invention, the source 604 and drain 606 include heavily boron dopedsource and drain regions. Alternatively, the source/drain 604/606 can beformed by incorporating dopants into the substrate 602.

FET Oxide layer 610 can be formed over the source 604 and drain 606 andaround the gate dielectric 608. The FET oxide layer 610 can include, forexample, a low-k dielectric oxide. In some embodiments of the invention,FET oxide layer 610 includes tetra-ethyl orthosilicate (TEOS) oxide.

Gate dielectric 608 can include any insulating material that issensitive to pH. In some embodiments of the invention, gate dielectricincludes hafnium dioxide (HfO₂), aluminum oxide (Al₂O₃), vanadium oxide(V₂O₅), titanium oxide (TiO₂), tungsten oxides, or combinations thereof.In some embodiments of the invention, in operation, gate dielectric 608includes a FET sensing surface 614 (the external surface of the gatedielectric) for determining local pH of tissue. In some embodiments ofthe invention, gate dielectric 608 is composed of HfO₂. In operation,extracellular fluid 504 forms the gate of the FET device. Theextracellular fluid 504 can be in contact with a plurality of cells 502.

In some embodiments of the invention, FET-pH sensors do not include ametal gate. In some embodiments of the invention, the gate dielectricforms the FET sensing surface in contact with the extracellular medium.In operation, the FET-pH sensor reference electrode is also in contactwith the extracellular medium in some embodiments of the invention.

The FET sensing 614 surface can have any shape. The sensing surface canhave a length or diameter of 5 to 15 micrometers (μm), for example from5 to 10 μm or from 5 to 8 μm. In some embodiments of the invention, theFET sensing surface has a length or diameter smaller than the diameterof a cell. For example, a cell can have a diameter of 10 μm and the FETsensing surface 614 can have a diameter of 5 μm.

Sensing of pH with a FET-pH sensor can be performed in accordance withknown methods. In operation, according to some embodiments of theinvention, the sensing signal is a drain current I_(D). Measurements canbe made by setting the reference electrode voltage equal to a gatevoltage, setting the drain to a small voltage (e.g., |30 mV|) andsetting the source voltage to 0 V. The silicon substrate can be set to 0V at the back side. A device including a FET-pH sensor can be applied toa solution or extracellular medium such that a sensing surface andreference electrode are exposed to the fluid. Measurements of draincurrent can be taken and used to determine local pH.

In some embodiments of the invention, an apparatus including a FET-pHsensor can be calibrated to determine sensing signal dependence onvoltage and pH. After calibration, drain current can be measured at afixed voltage and pH calculated therefrom.

FIG. 9 is a chart depicting drain current (I_(D)) versus gate voltageV_(SOL) of an exemplary FET-pH sensor for use in embodiments of thepresent invention. FIG. 5 demonstrates sensing signal (I_(D)) dependenceon gate voltage and pH. Buffered solutions, such as phosphate buffer of100 mM concentration, having known pH values of 4, 5.4, 6, 7, and 8 caneach be applied to a FET-pH sensor, such as a FET-pH sensor of a tip ofan apparatus for use in embodiments of the present invention. I_(D) canbe measured and plotted against the gate voltage V_(SOL). FIG. 5illustrates a FET-pH sensor with a voltage per pH unit of 58 mV.

In some embodiments of the invention, calibration results are used todetermine a local pH of a tissue of interest. For example, a fixedapplied voltage can be applied to a system having one or more FET-pHsensors and a sensing signal (I_(D)) can be measured in real time. Fromthe sensing signal, pH can readily be calculated with the calibrationresults.

FIG. 10 is a chart depicting drain current at a fixed voltage of 0.0.55V versus pH for the exemplary FET-pH sensor represented in FIG. 9.Application of a fixed voltage and measurement of sensing signal canprovide a pH measurement in real time.

As is illustrated in FIGS. 9 and 10, the sensing signal of embodimentsof the invention can result in a system with high sensitivity. Moreover,some embodiments of the invention including FET-pH sensors are sensitiveto H⁺ only. For example, FET-pH sensors including HfO₂ can be sensitiveto H⁺ only. In some embodiments, desirably, systems and apparatus use alow sensing voltage, such as a voltage of less than 1 V.

Embodiments of the present invention can provide a number of technicalfeatures and benefits. For example, embodiments of the present inventioncan provide real-time pH measurements with high spatial resolution fordetection and identification of cancerous cells during surgery. Suchmeasurements can improve surgical outcomes and patient comfort andreduce medical costs associated with cancer treatment, for example, byreducing the need for repeated surgical procedures, reducing the needfor repeated laboratory testing of tissue samples, and by reducing thetime expended by medical personnel during surgical excision.

FIG. 11 is a flow diagram of a method for removing cancerous tissue 700according to one or more embodiments of the present invention. As isshown at block 702, the method includes placing an apparatus for removalof cancerous cells in contact with an extracellular medium associatedwith a tissue of interest on a patient. The tissue of interest can be,for example, skin tissue. The method 700 includes, as shown at block704, measuring a local pH of the extracellular medium. The method 700includes determining whether the local pH is acidic, as is shown atdecision block 706. Responsive to a determination that the local pH isnot acidic, the method 700 can return to block 702. Responsive to adetermination that the local pH is acidic, the method 700 includesexcising the tissue of interest, as shown at block 708.

FIG. 12 is a flow diagram of a method for identifying cancerous tissuewith a surgical apparatus 800 in accordance with one or more embodimentsof the present invention. The method 800 includes, as is shown at block802, receiving a signal from a BJT-pH sensor applied to extracellularmedium of a tissue of interest. The method 800 also includes, as shownat block 804, setting the voltage of a collector and reference electrodeto zero. The method 800 also includes, as shown at block 806, holdingthe emitter of the BJT-pH sensor at a constant voltage. As shown atblock 808, the method 800 includes measuring collector current. Themethod 800 also includes, as shown at block 810, calculating a local pHbased upon collector current. As shown at block 812, the method 800includes outputting the local pH to a display.

Referring to FIG. 13, there is shown an embodiment of a processingsystem 100 for implementing the teachings herein. In this embodiment,the system 100 has one or more central processing units (processors) 101a, 101 b, 101 c, etc. (collectively or generically referred to asprocessor(s) 101). In one embodiment, each processor 101 can include areduced instruction set computer (RISC) microprocessor. Processors 101are coupled to system memory 114 and various other components via asystem bus 113. Read only memory (ROM) 102 is coupled to the system bus113 and can include a basic input/output system (BIOS), which controlscertain basic functions of system 100.

FIG. 13 further depicts an input/output (I/O) adapter 107 and a networkadapter 106 coupled to the system bus 113. I/O adapter 107 can be asmall computer system interface (SCSI) adapter that communicates with ahard disk 103 and/or tape storage drive 105 or any other similarcomponent. I/O adapter 107, hard disk 103, and tape storage device 105are collectively referred to herein as mass storage 104. Operatingsystem 120 for execution on the processing system 100 can be stored inmass storage 104. A network adapter 106 interconnects bus 113 with anoutside network 116 enabling data processing system 100 to communicatewith other such systems. A screen (e.g., a display monitor) 115 isconnected to system bus 113 by display adaptor 112, which can include agraphics adapter to improve the performance of graphics intensiveapplications and a video controller. In one embodiment, adapters 107,106, and 112 can be connected to one or more I/O busses that areconnected to system bus 113 via an intermediate bus bridge (not shown).Suitable I/O buses for connecting peripheral devices such as hard diskcontrollers, network adapters, and graphics adapters typically includecommon protocols, such as the Peripheral Component Interconnect (PCI).Additional input/output devices are shown as connected to system bus 113via user interface adapter 108 and display adapter 112. A keyboard 109,mouse 110, and speaker 111 all interconnected to bus 113 via userinterface adapter 108, which can include, for example, a Super I/O chipintegrating multiple device adapters into a single integrated circuit.

In exemplary embodiments of the invention, the processing system 100includes a graphics processing unit 130. Graphics processing unit 130 isa specialized electronic circuit designed to manipulate and alter memoryto accelerate the creation of images in a frame buffer intended foroutput to a display. In general, graphics processing unit 130 is veryefficient at manipulating computer graphics and image processing, andhas a highly parallel structure that makes it more effective thangeneral-purpose CPUs for algorithms where processing of large blocks ofdata is done in parallel.

Thus, as configured in FIG. 13, the system 100 includes processingcapability in the form of processors 101, storage capability includingsystem memory 114 and mass storage 104, input means such as keyboard 109and mouse 110, and output capability including speaker 111 and display115. In one embodiment, a portion of system memory 114 and mass storage104 collectively store an operating system such as the AIX® operatingsystem from IBM Corporation to coordinate the functions of the variouscomponents shown in FIG. 13.

The following definitions and abbreviations are to be used for theinterpretation of the claims and the specification. As used herein, theterms “comprises,” “comprising,” “includes,” “including,” “has,”“having,” “contains” or “containing,” or any other variation thereof,are intended to cover a non-exclusive inclusion. For example, acomposition, a mixture, process, method, article, or apparatus thatcomprises a list of elements is not necessarily limited to only thoseelements but can include other elements not expressly listed or inherentto such composition, mixture, process, method, article, or apparatus.

As used herein, the articles “a” and “an” preceding an element orcomponent are intended to be nonrestrictive regarding the number ofinstances (i.e. occurrences) of the element or component. Therefore, “a”or “an” should be read to include one or at least one, and the singularword form of the element or component also includes the plural unlessthe number is obviously meant to be singular.

As used herein, the terms “invention” or “present invention” arenon-limiting terms and not intended to refer to any single aspect of theparticular invention but encompass all possible aspects as described inthe specification and the claims.

As used herein, the term “about” modifying the quantity of aningredient, component, or reactant of the invention employed refers tovariation in the numerical quantity that can occur, for example, throughtypical measuring and liquid handling procedures used for makingconcentrates or solutions. Furthermore, variation can occur frominadvertent error in measuring procedures, differences in themanufacture, source, or purity of the ingredients employed to make thecompositions or carry out the methods, and the like. In one aspect, theterm “about” means within 10% of the reported numerical value. Inanother aspect, the term “about” means within 5% of the reportednumerical value. Yet, in another aspect, the term “about” means within10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of the reported numerical value.

The present invention can be a system, a method, and/or a computerprogram product at any possible technical detail level of integration.The computer program product can include a computer readable storagemedium (or media) having computer readable program instructions thereonfor causing a processor to carry out aspects of the present invention.

The computer readable storage medium can be a tangible device that canretain and store instructions for use by an instruction executiondevice. The computer readable storage medium can be, for example, but isnot limited to, an electronic storage device, a magnetic storage device,an optical storage device, an electromagnetic storage device, asemiconductor storage device, or any suitable combination of theforegoing. A non-exhaustive list of more specific examples of thecomputer readable storage medium includes the following: a portablecomputer diskette, a hard disk, a random access memory (RAM), aread-only memory (ROM), an erasable programmable read-only memory (EPROMor Flash memory), a static random access memory (SRAM), a portablecompact disc read-only memory (CD-ROM), a digital versatile disk (DVD),a memory stick, a floppy disk, a mechanically encoded device such aspunch-cards or raised structures in a groove having instructionsrecorded thereon, and any suitable combination of the foregoing. Acomputer readable storage medium, as used herein, is not to be construedas being transitory signals per se, such as radio waves or other freelypropagating electromagnetic waves, electromagnetic waves propagatingthrough a waveguide or other transmission media (e.g., light pulsespassing through a fiber-optic cable), or electrical signals transmittedthrough a wire.

Computer readable program instructions described herein can bedownloaded to respective computing/processing devices from a computerreadable storage medium or to an external computer or external storagedevice via a network, for example, the Internet, a local area network, awide area network and/or a wireless network. The network can comprisecopper transmission cables, optical transmission fibers, wirelesstransmission, routers, firewalls, switches, gateway computers and/oredge servers. A network adapter card or network interface in eachcomputing/processing device receives computer readable programinstructions from the network and forwards the computer readable programinstructions for storage in a computer readable storage medium withinthe respective computing/processing device.

Computer readable program instructions for carrying out operations ofthe present invention can be assembler instructions,instruction-set-architecture (ISA) instructions, machine instructions,machine dependent instructions, microcode, firmware instructions,state-setting data, configuration data for integrated circuitry, oreither source code or object code written in any combination of one ormore programming languages, including an object oriented programminglanguage such as Smalltalk, C++, or the like, and procedural programminglanguages, such as the “C” programming language or similar programminglanguages. The computer readable program instructions can executeentirely on the user's computer, partly on the user's computer, as astand-alone software package, partly on the user's computer and partlyon a remote computer or entirely on the remote computer or server. Inthe latter scenario, the remote computer can be connected to the user'scomputer through any type of network, including a local area network(LAN) or a wide area network (WAN), or the connection can be made to anexternal computer (for example, through the Internet using an InternetService Provider). In some embodiments of the invention, electroniccircuitry including, for example, programmable logic circuitry,field-programmable gate arrays (FPGA), or programmable logic arrays(PLA) can execute the computer readable program instructions byutilizing state information of the computer readable programinstructions to personalize the electronic circuitry, in order toperform aspects of the present invention.

Aspects of the present invention are described herein with reference toflowchart illustrations and/or block diagrams of methods, apparatus(systems), and computer program products according to embodiments of theinvention. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer readable program instructions.

These computer readable program instructions can be provided to aprocessor of a general purpose computer, special purpose computer, orother programmable data processing apparatus to produce a machine, suchthat the instructions, which execute via the processor of the computeror other programmable data processing apparatus, create means forimplementing the functions/acts specified in the flowchart and/or blockdiagram block or blocks. These computer readable program instructionscan also be stored in a computer readable storage medium that can directa computer, a programmable data processing apparatus, and/or otherdevices to function in a particular manner, such that the computerreadable storage medium having instructions stored therein comprises anarticle of manufacture including instructions which implement aspects ofthe function/act specified in the flowchart and/or block diagram blockor blocks.

The computer readable program instructions can also be loaded onto acomputer, other programmable data processing apparatus, or other deviceto cause a series of operational steps to be performed on the computer,other programmable apparatus or other device to produce a computerimplemented process, such that the instructions which execute on thecomputer, other programmable apparatus, or other device implement thefunctions/acts specified in the flowchart and/or block diagram block orblocks.

The flowchart and block diagrams in the Figures illustrate thearchitecture, functionality, and operation of possible implementationsof systems, methods, and computer program products according to variousembodiments of the present invention. In this regard, each block in theflowchart or block diagrams can represent a module, segment, or portionof instructions, which comprises one or more executable instructions forimplementing the specified logical function(s). In some alternativeimplementations, the functions noted in the blocks can occur out of theorder noted in the Figures. For example, two blocks shown in successioncan, in fact, be executed substantially concurrently, or the blocks cansometimes be executed in the reverse order, depending upon thefunctionality involved. It will also be noted that each block of theblock diagrams and/or flowchart illustration, and combinations of blocksin the block diagrams and/or flowchart illustration, can be implementedby special purpose hardware-based systems that perform the specifiedfunctions or acts or carry out combinations of special purpose hardwareand computer instructions.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments described. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdescribed herein.

What is claimed is:
 1. A method for identification and removal ofcancerous tissue, comprising: placing an apparatus for removal ofcancerous cells in contact with an extracellular medium associated witha tissue of interest on a patient, wherein the apparatus comprises: adisplay; an apparatus tip comprising an array of bipolar junctiontransistor-pH (BJT-pH) sensors, the apparatus tip comprising a length of2 to 10 mm and a width of 2 to 10 mm, each BJT-pH sensor comprising: asensing surface positioned on a surface of an oxide layer, the sensingsurface having a diameter of 5 to 15 micrometers; a BJT base; and aconductive line embedded in the oxide layer, the conductive linepositioned between a bottom surface of the sensing surface and a topsurface of the BJT base; and automation circuitry comprising aprocessing unit in communication with the apparatus tip and the display;measuring a local pH of the extracellular medium with the apparatus;determining in real-time a boundary of a cancerous region, wherein theboundary comprises spatial data at a spatial resolution defined by thearray of BJT-pH sensors, wherein an area of the sensing surface isproportional to the spatial resolution; and based upon a determinationthat the local pH is acidic, excising the tissue of interest within thecancerous region.
 2. The method of claim 1, wherein each of the BJT-pHsensors further comprise: a reference electrode positioned on a surfaceof the oxide layer; a collector; and an emitter on the top surface ofthe BJT base.
 3. The method of claim 2, wherein measuring the local pHof the extracellular medium further comprises: applying zero voltage tothe collector; applying zero voltage to the reference electrode;applying a voltage to the emitter; and measuring a collector currentfrom the collector.
 4. The method of claim 1, wherein the automationcircuitry is configured to calibrate the BJT-pH sensors and to measurepH in real-time.